tbuckley/cabot-search huggingface dataset:
CTIM-18. PHASE 2 STUDY OF PD-1 BLOCKADE WITH PEMBROLIZUMAB PLUS RE-IRRADIATION FOR RECURRENT GLIOBLASTOMA (RGBM) (NCT03661723)
Authors: Fabio Iwamoto, Shyam Tanguturi, Arati Desai, Lakshmi Nayak, Erik Uhlmann, Tony Wang, Robert Lustig, Lauren Hertan, Stephen Bagley, Julia Hayden, Corey Laforest-Roys, Alona Muzikansky, Christine McCluskey, Ugonma Chukwueke, J Ricardo McFaline-Figueroa, Eudocia Lee, Patrick Y Wen, David Reardon
Journal: Neuro-Oncology (2022)

Abstract Re-irradiation is therapeutically considered for select rGBM patients and may induce immunogenic cell death to stimulate anti-tumor immune responses. Our phase 2 study of re-irradiation with pembrolizumab among rGBM patients evaluated the efficacy and safety of this regimen. METHODS Adult rGBM patients with KPS ≥ 70, a maximum supratentorial tumor diameter of 6 cm who were on ≤ 2mg dexamethasone/day and were ≥ 6 months from initial conventional radiation therapy were eligible. Cohort A (bevacizumab [BEV]-naïve) had ≤ 2 prior progressions while cohort B (BEV-refractory) allowed unlimited progressions but only one on prior BEV. Re-irradiation included 35 Gy over 10 fractions to residual enhancing (cohort A) as well as enhancing + non-enhancing (cohort B) disease. Pembrolizumab was administered at 200 mg every three weeks beginning within one week of re-irradiation start. BEV was administered at 15 mg/kg every three weeks for cohort B only. RESULTS Sixty patients enrolled (n = 30 per cohort) with a median age of 61 years (range 20-76), 47% were female and 53% enrolled after 2 or more progressions. Grade 3 events deemed at least possibly related to study therapy in &amp;gt; one patient for cohort A included headache (n = 2) and for cohort B included elevated ALT (n = 2) and hypertension (n = 5). No grade 4 events occurred in more than single patients per cohort and no grade 5 events occurred. Median PFS and PFS-6 were 4.9 months (95% CI: 3.5, 5.6) and 26.0% (95% CI: 12.3%, 43.0%) for cohort A and 4.14 months (95% CI: 3.45, 5.42) and 16.9% (95% CI: 5.4, 33.7) for cohort B. Median survival for cohorts A and B were 11.5 months (95% CI: 9.6, 14.1) and 7.6 months (95% CI 5.5, 9.3), respectively. CONCLUSIONS Re-irradiation with pembrolizumab was overall well tolerated and achieved comparable efficacy to historical salvage therapy established with lomustine.
QLTI-19. EVALUATION OF INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSTIC SERVICES – A LARGE TERTIARY UK CENTRE EXPERIENCE
Authors: Richard Digby, Piravin Ramakrishnan, Saad Moughal, Arundhati Chakrabarty, Ryan Mathew
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Brain tumour intraoperative diagnosis (smear cytology, frozen section) is a commonly performed, routine diagnostic service. Currently, samples must be transported from the operating room (OR) to pathology, impacting turnaround time (TAT), carbon emissions (if cross-site), and motivation for repeat sampling. We performed a broad evaluation of current practice in a large, tertiary, UK brain tumour centre, to identify potential gains in real-time tissue diagnosis. METHODS All brain tumour samples (n=228) sent for intraoperative diagnosis in 2021 were analysed retrospectively. TAT was assessed by capturing different timepoints along the pathway. Concordance between diagnoses at the following stages was determined: preoperatively based on radiology, intraoperatively (frozen section or smear), provisional paraffin and final integrated. Additionally, we anonymously surveyed neurosurgeons’ opinions (n=18) on the current service. RESULTS The mean (±SD) specimen transportation time was 10.6±2.0 minutes, with an estimated total TAT of 30-60 minutes. Intraoperative diagnosis provided a slightly higher rate of concordance with provisional paraffin diagnosis than preoperative radiological diagnosis (89.5% vs 86.3%). Non-concordance was most commonly due to non-representative sampling (e.g., predominantly necrotic), with no repeat sample being sent/available intraoperatively. Prevailing neurosurgical opinion of the intraoperative diagnostic service was dissatisfaction or neutrality (50% and 39% of respondents), with a minority being positive (11%). Reasons for this included: intraoperative delay due to TAT (47%), perceived inaccuracy of results (41%), and perceived reduced out-of-hours availability (56%). CONCLUSIONS Current brain tumour intraoperative diagnostic practice relies on physical sample transportation and manual processing; the resultant long TAT causes surgeon dissatisfaction and dissuades repeat analysis in the case of non-representative sampling. Real-time tissue diagnostic technologies such as OR-sited probe-based confocal endomicroscopy, scanners and Raman spectroscopy should be considered to facilitate faster and repeated examination. The latter may have additional benefits in real-time expert pathology feedback, tumour margin-zone analysis and increased extent of resection.
QLTI-15. VENOUS SINUS THROMBOSIS AFTER BRAIN TUMOR RESECTION
Authors: Patrick Regis, Robert Cavaliere, Eric Sauvageau, Ricardo Hanel
Journal: Neuro-Oncology (2022)

Abstract Post-operative venous sinus thrombosis (POVST) is an uncommon complication from a craniotomy for brain tumor resection. There are few data in how to treat POVST, including the use of anticoagulation and follow-up. It has been found that POVST is more common in dural-based lesions especially located on or near a sinus, however treatment has not been standardized. We retrospectively reviewed our POVST cases between January 2018 to December 2020 for brain tumor resection, whether we chose to start anticoagulation or not, and the eventual outcome. We also performed a literature review on the topic to compare findings and management. We identified 14 cases of POVST; 8 of the cases were for extra-axial masses. Of the 14, 6 POVST had clot involving the superior sagittal sinus (SSS), with 3 being discharged with a direct oral anticoagulant (DOAC) and one being discharged on warfarin. With transverse sinus involvement, 6 cases were noted (with no SSS clot), with 2 started on a DOAC and 2 being started on ASA 81mg. In the sigmoid sinus there were 2 cases and did not receive anticoagulation. Of the 14 total cases, 1 was symptomatic (new-onset seizures) necessitating surgical recanalization and no other cases had symptoms attributed to the POVST. Two patients died from unrelated reasons prior to receiving any outpatient imaging, and all other patients had recanalization of their involved sinuses within 2-5 months. There were no complications in patients receiving anticoagulation. Our literature review didn't show a standardized method in POVST treatment. There is also disagreement in what anticoagulation should be used, and if it is necessary. Based on our retrospective analysis and literature review, if the clot is symptomatic, involves the SSS, or propagates, we recommend anticoagulation. Outside the SSS, it should be determined on a case-by-case basis, but anticoagulation may not be necessary.
NIMG-78. DEVELOPMENT OF A PRECLINICAL GLIOBLASTOMA MURINE MODEL FOR THE ASSESSMENT OF RADIATION NECROSIS USING DIFFUSION KURTOSIS IMAGING
Authors: Connor Stephenson, Daniel G McDonald, Milad Yazdani, Shikhar Mehrotra, Cynthia A Welsh, Libby Kosnik Infinger, William A Vandergrift, Abhay K Varma, Sunil J Patel, Pierre Giglio, Alicia Zukas, David Cachia, Scott M Lindhorst, Arabinda Das
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GB) patients often present with either radiation-induced necrosis (RN) or develop tumor recurrence (TR). Radiologically, differentiating between these two disease states is particularly difficult, especially utilizing traditional MRI techniques. Accurately distinguishing these separate states is important, as failure to do so can ultimately lead to unnecessary surgical intervention or early cessation of appropriate radiation therapy. Currently, distinction between these pathologies is made using best clinical judgement by the neuro-oncology team. Therefore, there is a need for developing novel non-invasive techniques that can reliably distinguish between radiation necrosis and tumor recurrence. Primary data was collected utilizing orthotopically transplanted GL261 mouse GB cells in a C57BL/6 mouse. Tumor induction was verified by MRI after two weeks. RN and TR were initiated using an aggressive radiation dose fractionation (12 Gy or 60 Gy). This was completed using a 4 mm radiation cone such that one portion of the tumor received 100% dose of 12 Gy or 60 Gy fraction which is sufficient to cause RN, whereas the tumor edge received only 50% of the dose, allowing for tumor recurrence. Our data demonstrated mice tumor recurrence and radiation necrosis on MRI imaging. Axial T2-weighted MRI and DKI sequence at 2 weeks following implantation demonstrated edema compatible with tumor recurrence. One week later, the T2-weighted MRI and DKI sequences demonstrated continued tumor progression. In a separate mouse with orthotopic glioblastoma implantation with high dose (60 Gy) radiation treatment, T2 imaging and DKI demonstrated areas of tumor and suspected central radiation necrosis. DKI imaging biomarkers was compared by liquid biopsy, H&amp;E staining, and Immunohistochemistry (IHC) analysis of sacrificed mice. Our H&amp;E staining results showed typical pathological features of GB and RN, and TR in each case. This result demonstrated that our proposed model for radiation induction was effective at achieving its goal.
IMMU-16. SOMATIC MUTATIONS IN HUMAN LEUKOCYTE ANTIGEN GENES AND ANTIGEN PRESENTATION PATHWAY GENES IN MALIGNANT GLIOMA
Authors: Sara Schulte, Peter Trojok, Moritz Schäfer, Wolfgang Peter, Manfred Westphal, Katrin Lamszus, Alexander Dilthey, Malte Mohme
Journal: Neuro-Oncology (2022)

Abstract Immunotherapeutic approaches in cancer aim to booster T cell mediated immune responses. Tumor-specific T cells recognize target cells via human leukocyte antigen (HLA) molecules before cell specific lysis is initiated. Malignant gliomas are known for their immunoevasive and immunosuppressive properties which impede effective tumor-specific immune responses, including clinical responses to immune checkpoint inhibition. Our aim was to investigate whether somatic mutation in HLA genes and antigen presentation pathway genes are present in malignant gliomas. METHODS We performed next generation sequencing in 138 patients, including matched tumor and blood samples from 100 IDHwt glioblastomas, 25 IDHmut astrocytomas and 13 IDHmut oligodendrogliomas. Sequencing was performed on tumor and peripheral blood for HLA class I (HLA-A, -B, -C), HLA class II (HLA-DR, -DP, -DQ), non-classical HLA molecules (HLA-E, -F, -G, -H), MICA/B, TAP1/2 and beta2 microglobulin (B2M). Identified calls were validated using targeted nanopore sequencing. RESULTS In total, we identified 28 mutations based on Illumina sequencing. Mutations were located in HLA-B (2 mutations), HLA-C (1), B2M (2), HLA-DQA1 (4), HLA-DQB1 (4), HLA-DPB1 (1), HLA-E (1), HLA-F (2), HLA-G (3), HLA-H (1), MICA (3), MICB (2), TAP1 (1) and TAP2 (1). No mutations were found in HLA-A and HLA-DRB1. A frequency cutoff of 5% was applied. Additional mutations (n = 46) below this cutoff were identified. The mutations were found in 30 patients (21.7%). Some patients harbored up to 7-8 mutations in multiple HLA and antigen presenting pathway genes. Most mutations were found in the MICA (MHC class I polypeptide–related sequence A) gene locus, which is engaged by the NKG2D ligand which is broadly expressed on NK cells, gd and ab T cells. CONCLUSION Our study demonstrates that somatic mutations in HLA and antigen presentation pathway genes are frequently present in malignant gliomas.
CTNI-15. REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2)
Authors: Marta Padovan, Gian Luca De Salvo, Antonio D'Avolio, Mario Caccese, Vittorina Zagonel, Giuseppe Lombardi
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) has activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneously xenografts. This phase I open-label multicentric study will evaluate the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ+RT as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in those two cohorts. Secondary objectives are: assessment of pharmacokinetics of REG, TMZ and possible pharmacokinetic interactions between TMZ and REG (cohort A); assessment of preliminary antitumor activity; evaluation of quality of life during the treatment. The dose escalation will be explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg; level -1 40 mg will be evaluated in case of Dose-Limiting Toxicity (DLT) during REG 80 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ+RT (60 Gy/30 fractions); in the adjuvant phase of cohort B, REG will be given (in association to TMZ) at MTD shown in the prior adjuvant phase dose escalation.The DLT evaluation period will be two cycles from the start of cycle 1 of adjuvant or from day 1 to last day of the concomitant phase. Approximately 36 subjects will be enrolled.
EPCO-18. UNSUPERVISED MACHINE LEARNING ON TUMOR IMMUNE TRANSCRIPTOMIC DATA REVEALS DISTINCT IMMUNOLOGIC SUBTYPES OF GLIOBLASTOMA
Authors: Alexander F Haddad, Jia Shu Chen, Sudheesha Perera, Anvith Reddy, Vardhaan Ambati, Manish Aghi
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) has demonstrated a limited therapeutic response to single-agent immunotherapies, highlighting the need for a better understanding of GBM tumor immune phenotypes to inform targeted immunologic treatments. To elucidate GBM immunologic phenotypes we performed unsupervised machine learning on microarray transcriptomic data from 815 newly diagnosed GBM patients. We utilized immune genes only and performed k-means clustering for k=2-10 with within-cluster sum of squares and silhouette methods used to identify the optimal number of clusters. Identified subtypes were further characterized using xCell to estimate the tumor infiltration of 64 immune and stromal cell types. Two primary immunologic subtypes were identified: subtype 1 (423 patients) and subtype 2 (392 patients). There was no difference in patient age (mean age 58 years) or gender between subtypes. Subtype 1 was primarily classical subtype GBMs (50.5%, p&amp;lt; 0.001), while subtype 2 was composed of primarily mesenchymal subtype GBMs (74.2%). Relative to subtype 1, subtype 2 was characterized by high expression of immune checkpoint and co-stimulatory proteins, including CD86, OX40L, IDO1, and LAG3. Subtype 2 also had increased activation of immune genes associated with cytolytic activity and antigen processing. In addition, subtype 2 had increased infiltration of M2 macrophages, monocytes, dendritic cells, and neutrophils while subtype 1 had higher infiltration of CD8 naïve T cells. Multivariate logistic regression confirmed that subtype 2 was characterized by monocytes, M1 and M2 macrophages, neutrophils, and dendritic cells while subtype 1 was characterized by CD8 naïve T cells, regulatory T cells, and naive B cells. Subtype 2 had reduced progression-free survival, but there was no difference in overall survival between the two subtypes. In summary, unsupervised machine learning of GBM immune transcriptomic data identified two immune phenotypes, one of which was more immunologically active than the other, potentially informing future personalized immunotherapy treatments.
EXTH-59. IMMORTALIZATION OF MOUSE BONE MARROW-DERIVED MACROPHAGES FOR BRAIN TUMOR THERAPY DEVELOPMENT
Authors: Benson Joseph, Liu Ann, Chirag Patil, Keith Black, Tao Sun
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Macrophages can cross blood-brain-barrier (BBB) and infiltrate brain parenchyma with malignancies such as glioma. Recently, many efforts have been made to develop macrophage-based cancer therapy, including CAR–macrophages. However, lack of proliferation in differentiated macrophages hinders their utility. We sought to ameliorate this problem by immortalizing macrophages to assist potential therapy development. Bone marrow derived macrophages (BMDMs) were harvested from C57Bl/6 mice and transduced with mouse telomerase reverse transcriptase (mTert) gene via retrovirus. Following puromycin selection, morphology, proliferation, lineage marker expression and phagocytosis were measured by microscopy, flow cytometry and IncuCyte assays. RESULTS Through overexpression of mTert, we have successfully immortalized mouse BMDMs, termed as iBMDMs. Morphologically, iBMDMs largely maintained features of primary BMDMs. The established iBMDMs proliferated for over 20 subcultures without obvious reduction in growth. Proliferation of iBMDMs (doubling time, dt=52h) was similar to IC-21(dt=53h), an established mouse macrophage line immortalized by SV40-T antigen, and slower than Raw264.7 (dt=23h), an immortalized mouse macrophage line driven by murine leukemia virus. Furthermore, iBMDMs can grow without macrophage colony-stimulating factor (M-CSF) (dt=54h). Macrophage lineage markers CD11B and F4/80 expression levels were higher in primary BMDMs (CD11B+=62.8±0.53%, F4/80+=54.9±0.38%, CD11B+F4/80+=52.7±0.41%, n=2 for all flow results) and iBMDMs (CD11B+=39.1±5.29%, F4/80+=26.4±7.93%, CD11B+F4/80+=24.6±5.95%) than in IC-21 (CD11B+=10.7±0.37%, F4/80+=19.4±1.88%, CD11B+F4/80+=9.13±0.37%) and Raw264.7 (CD11B+=34.3±5.32%, F4/80+=14.1±4.40%, CD11B+F4/80+=8.33±4.19%) cells lines. Lastly, we evaluated the phagocytic ability of iBMDMs through IncuCyte assays. Similar to primary BMDMs, we observed a concentration dependent increase in red fluorescence, which indicates the phagocytosis of E. coli derived bioparticles, in iBMDMs with and without M-CSF. CONCLUSIONS We immortalized bone marrow-derived macrophages of C57Bl/6 mouse origin with competent immune function via mTert transduction. These cells can be used in preclinical immunotherapy development for glioma treatment. Ongoing work is focused on assessing their ability to penetrate BBB and infiltrate brain tumor in a mouse glioma model.
RADT-40. RADIATION-INDUCED CONTRAST ENHANCEMENT FOLLOWING PROTON RADIOTHERAPY FOR LOW-GRADE GLIOMA DEPENDS ON TUMOR CHARACTERISTICS AND IS RARER IN CHILDREN THAN ADULTS
Authors: Tanja Eichkorn, Julia Bauer, Maximilian Deng, Emanuel Bahn, Jonathan Lischalk, Meixner Eva, Sandrini Elisabetta, Sebastian Regnery, Thomas Held, Hoerner-Rieber Juliane, Markus Alber, Herfarth Klaus, Debus Juergen, Harrabi Semi, Koenig Laila
Journal: Neuro-Oncology (2022)

Abstract Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) versus children (5%) (p = 0.0043). Also, within the adult cohort, RICE risk increases with age (p = 0,00128). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.
DNAR-13. SONIDEGIB AND GANT61 INDUCE DNA DAMAGE IN PEDIATRIC SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Laura Price, Bonnie Lau
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of all pediatric brain tumors. The current standard of care includes both craniospinal and focal radiation therapy which leads to long term consequences in the pediatric population such as bone and tissue hypoplasia, decreased neurocognitive functioning, as well as an increased risk for secondary radiation induced cancers. Thus, there is a need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing radiation toxicity in healthy tissue in the pediatric patient population. The dysregulation and constitutive activation of the Sonic Hedgehog (SHH) signaling pathway accounts for ~30% of all medulloblastomas. In addition to playing a role in tumorigenesis, the SHH pathway is known to play a role in the radiation sensitivity and risk of tumor recurrence. We hypothesize that inhibiting the SHH pathway at Smoothened (Smo) or Gli1 will increase DNA damage, resulting in increased cell killing following radiation therapy. We found that treatment of medulloblastoma cells with the drug Sonidegib or GANT61 decreased the expression of the respective targets Smo and Gli1. Both drugs also significantly decreased expression of FANCD2, a DNA damage repair gene essential for homologous recombination. Pretreatment with Sonidegib or GANT61 resulted functionally with decreased tumor cell viability and self-renewal following radiation. These data suggest that Smo and Gli1 inhibition are promising targets for increasing the radiation sensitivity of pediatric SHH medulloblastoma.